Melanoma Leading the Charge

The first biologic agent shown to have an overall survival (OS) benefit in unresectable or metastatic melanoma was ipilimumab (Yervoy), which was approved by the FDA in 2011.

“Since 2011, it’s been a whirlwind of progress and advancement, and melanoma has been leading the pack for immunotherapies, but now, we’re all trying to find the best way to use these new options,” Dr Anderson said.

Novel systemic treatment options for unresectable stage III or metastatic stage IV melanoma include immune checkpoint inhibitors and targeted therapy. The goal of these regimens is to add an OS benefit, but new agents and evolving indications may lead to uncertainty with treatment planning of first, second, or subsequent therapies, she said.

OS Updates in Immunotherapy

High-dose interleukin-2 achieved significant results in patients years ago, according to Dr Anderson, but currently it has a limited role because of more effective immunotherapy options. FDA-approved checkpoint inhibitors for advanced melanoma include ipilim­umab (a monoclonal antibody that binds to and prevents the interactions of cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4]) and the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo). Both of these PD-1 inhibitors are National Comprehensive Cancer Network category 1 recommendations as first-line therapy for advanced melanoma. Dual checkpoint blockade with CTLA-4 and PD-1 inhibition is another effective treatment option.

Monotherapy with pembrolizumab or nivolumab has similar efficacy, but some patients have certain comorbidities (eg, autoimmune disorders) that render them unable to be treated with these therapies because of the risk for serious and potentially fatal adverse events. This risk is compounded with dual checkpoint blockade therapy.

“So there is a definite need to better understand what patient or disease characteristics will confer the greatest benefit in the advanced melanoma population,” Dr Anderson said.

Ipilimumab has the most complete long-term survival data available to date. The ipilimumab 3-mg/kg regimen is the only dose approved for unresectable or metastatic melanoma, whereas the ipilimumab 10-mg/kg regimen has a sole indication for adjuvant treatment of melanoma. A pooled analysis of OS data across 12 different phase 2 and phase 3 studies of ipilimumab, including >1800 treatment-naïve or previously treated patients who were observed for up to 10 years, revealed a median OS of 11.4 months and an estimated 3-year survival rate of 22%.

“What’s interesting is the primary analysis also reviewed 254 patients who were still alive at least 3 years after receiving ipilimumab, and they found that the OS curve started to plateau at year 3 and extended for the duration of follow-up, up to year 10. So, this suggested that once [the patients] hit year 3, if they’re alive and doing well, this is a milestone time point for them,” Dr Anderson explained.

Improving the Standard of Care

The KEYNOTE-006 clinical trial was the first head-to-head comparison of the PD-1 inhibitor pembrolizumab (10 mg/kg intravenously [IV] every 2 or 3 weeks) to ipilimumab (3 mg/kg IV every 3 weeks) for advanced melanoma. Of 834 patients enrolled, OS at 2 years was 55% in both pembrolizumab arms versus 43% with ipilimumab.

Twice as many patients experienced progression-free survival at 2 years with pembrolizumab versus ipilimumab, and objective responses, complete responses, and rates of disease control were all higher with pembrolizumab, “cementing its status as a preferred frontline immunotherapy agent,” Dr Anderson confirmed.

Updated OS data from the KEYNOTE-001 trial are based on 655 patients with advanced melanoma, over half of whom were previously treated with ipilimumab, and some who had received 3 lines of previous therapy. KEYNOTE-001 was a phase 1b study of pembrolizumab 2 or 10 mg/kg IV given every 2 or 3 weeks until disease progression or unacceptable toxicity.

The median OS was 23.8 months, with a median follow-up of 43.4 months. Three- and 4-year survival estimates were 42% and 37%, respectively, with higher rates of survival reported in the treatment-naïve patients. The median duration of treatment with pembroliz­umab was 6 months, with approximately 16% of patients still receiving treatment at the data cutoff date.

In the KEYNOTE-001 trial, 16% of patients with advanced melanoma were complete responders, with a median time to complete response of 12 months. A total of 87.6% of that subset had continued complete response after a median follow-up of 30 months, and the estimated 24-month disease-free survival rate after achieving a complete response was 90.9%.

“With that study we learned some important details about what factors may contribute to higher rates of complete response,” Dr Anderson explained, adding that some key questions still need to be answered. Subsequent trials should address issues including optimum duration of treatment to achieve and maintain a complete response, when it is appropriate to stop treatment after complete response, how various baseline factors may contribute to prognosis, and the likelihood of having a response with PD-1 inhibition, she noted.

A total of 945 patients were randomized in a 1:1:1 ratio. Median follow-up was longest in the combination arm, with a 3-year progression-free survival rate of 39%, compared with 32% for nivolumab monotherapy and 10% for ipilimumab monotherapy. OS rates at 3 years were 58% in the combination arm, 52% for nivolumab, and 34% for ipilimumab. Objective responses were also higher with combination therapy; 58% compared with 44% with nivolumab and 19% with ipilimumab. The median duration of response has still not been reached with either nivolumab monotherapy or nivolumab plus ipilimumab, but was 19.3 months with ipilimumab monotherapy.

Overall, grade 3 or 4 toxicities were much lower with nivolumab (21%) or ipilimumab (28%) when compared with combination therapy (59%).

“So, as can be expected, discontinuation related to treatment-associated effects were higher with combination therapy,” Dr Anderson noted.

The 3-year OS data reveal an OS benefit with nivolumab-based therapy (either monotherapy or in combination with ipilimumab) versus ipilimumab monotherapy. Although there were higher progression-free and OS rates with the combination arm compared with nivolumab monotherapy, the study was not powered to compare those 2 arms directly, so that is essentially just a descriptive analysis, Dr Anderson observed.

Based on the available data, the question still remains as to whether nivolumab plus ipilimumab provides a significant OS benefit compared with nivolumab monotherapy.

Strategies in the Adjuvant Setting

“With melanoma, we have to take advantage of any treatment momentum that we have, and this includes trying to move our effective immunotherapy regimens into the adjuvant setting, with the hopes of preventing a recurrence altogether,” Dr Anderson stated.

The EORTC 18071 phase 3 trial of adjuvant ipilimumab versus placebo in patients with resected stage III melanoma showed improved recurrence-free survival and OS, but this included a grade 3 or 4 adverse event rate of 54%, in addition to 5 treatment-related deaths.

“So, when you’re dealing with patients who currently have no evidence of disease, this level in severity of toxicities really has to be taken into account in treatment decision-making,” she noted.

In the CheckMate 238 trial of patients who had undergone a regional lymph node dissection, adjuvant treatment with nivolumab 3 mg/kg IV resulted in significantly longer 12-month recurrence-free survival than with ipilimumab 10 mg/kg IV. More than 60% of patients receiving nivolumab were able to complete the full year of treatment, compared with only 26.9% of patients who received ipilimumab.

“Ultimately, treatment-related adverse effects that led to discontinuation of therapy occurred much more often with ipilimumab than with nivolumab, clearly identifying which of the two is the better tolerated therapy,” Dr Anderson said.